Osteoclasts, which mediate bone resorption, are involved in normal and abnormal bone remodeling processes, including osteolytic disorders. Osteoclasts are multinucleated cells differentiating from haemopoietic cells. It is generally accepted that osteoclasts are formed by the fusion of mononuclear precursors derived from haemopoietic stem cells in the bone marrow, rather than incomplete cell division. The differentiation of osteoclast precursors into mature multinucleated osteoclasts requires different factors including hormonal and local stimuli and living bone and bone cells have been shown to play a critical role in osteoclast development. Osteoblastic or bone marrow stromal cells are also required for osteoclast differentiation. Osteoclasts are responsible for dissolving both the mineral and organic bone matrix. Osteoclasts represent terminally differentiated cells expressing a unique polarized morphology with specialized membrane areas and several membrane and cytoplasmic markers.
Several molecular mechanisms bring about cancer cells to metastasize to bone, and osteotropic cancer cells are believed to acquire bone cell-like properties which improve homing, adhesion, proliferation and survival in the bone microenvironment. Signaling pathways involved in tumor growth and development of osteolytic lesions include RANK, RANKL, osteoprotegerin (OPG), IGF and the membrane type (MT)-matrix metalloproteinases (MMPs). The initial phase of bone degradation consists of removal of the unmineralized type I collagenous layer followed by degradation of the mineralized matrix, which also comprises type I collagen. Tumor expansion in bone requires the removal of this matrix that is particularly abundant and resistant to degradation. The assistance of osteoclasts appears to be mandatory because osteoclasts are the primary cells involved in bone matrix solubilization. The capacity of osteoclasts to degrade bone resides in their ability to secrete protons, cathepsin K and MMPs. A generalized increase in MMPs levels within the bone environment when cancer cells are present is due, in part, to production of MMPs by the cancer cells themselves.
Since osteoclasts play a major role in osteolytic bone metastases and other osteolytic diseases, there is a need in the art for new agents and methods for preventing osteoclast stimulation and function. Several therapeutic strategies targeting osteolytic disease are currently being used or under development, where efforts have mainly focused on the development of drugs to block bone resorption through inhibiting the formation or activity of osteoclasts. The bisphosphonates (BPs), pyrophosphate analogs that concentrate in bone, are to date the most effective inhibitor of bone resorption. BPs are taken up by osteoclasts, inhibiting their activity and causing the cells to undergo apoptosis, thereby inhibiting bone resorption. Advanced cancers are prone to metastasize. Effective treatments for bone metastases are not yet available—existing treatments such as bisphosphonates, chemotherapy and radiotherapy improve the quality of life with no life-prolonging benefits and have significant side effects.